High-throughput screening identifies a novel natural product-inspired scaffold capable of inhibiting Clostridioides difficile in vitro

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dc.contributor.authorPal, Rushaen
dc.contributor.authorDai, Mingjien
dc.contributor.authorSeleem, Mohamed N.en
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.contributor.departmentCenter for Emerging, Zoonotic, and Arthropod-borne Pathogensen
dc.date.accessioned2021-08-05T18:11:51Zen
dc.date.available2021-08-05T18:11:51Zen
dc.date.issued2021-05-25en
dc.date.updated2021-08-05T18:11:47Zen
dc.description.abstractClostridioides difficile is an enteric pathogen responsible for causing debilitating diarrhea, mostly in hospitalized patients. The bacterium exploits on microbial dysbiosis induced by the use of antibiotics to establish infection that ranges from mild watery diarrhea to pseudomembranous colitis. The increased prevalence of the disease accompanied by exacerbated comorbidity and the paucity of anticlostridial drugs that can tackle recurrence entails novel therapeutic options. Here, we report new lead molecules with potent anticlostridial activity from the AnalytiCon NATx library featuring natural product-inspired or natural product-derived small molecules. A high-throughput whole-cell-based screening of 5000 synthetic compounds from the AnalytiCon NATx library helped us identify 10 compounds capable of inhibiting the pathogen. Out of these 10 hits, we found 3 compounds with potent activity against C. difficile (MIC = 0.5–2 μg/ml). Interestingly, these compounds had minimal to no effect on the indigenous intestinal microbial species tested, unlike the standard-of-care antibiotics vancomycin and fidaxomicin. Further in vitro investigation revealed that the compounds were nontoxic to Caco-2 cell line. Given their potent anticlostridial activity, natural product-inspired scaffolds may suggest potential avenues that can address the unmet needs in preventing C. difficile mediated disease.en
dc.description.versionPublished versionen
dc.format.extent7 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifierARTN 10913 (Article number)en
dc.identifier.doihttps://doi.org/10.1038/s41598-021-90314-3en
dc.identifier.eissn2045-2322en
dc.identifier.issn2045-2322en
dc.identifier.issue1en
dc.identifier.orcidSeleem, Mohamed [0000-0003-0939-0458]en
dc.identifier.other10.1038/s41598-021-90314-3 (PII)en
dc.identifier.pmid34035338 (pubmed)en
dc.identifier.urihttp://hdl.handle.net/10919/104586en
dc.identifier.volume11en
dc.language.isoenen
dc.publisherNature Researchen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000659136700001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectFECAL MICROBIOTA TRANSPLANTATIONen
dc.subjectLEAD DISCOVERY STRATEGIESen
dc.subjectINFECTIONen
dc.subjectCOLITISen
dc.titleHigh-throughput screening identifies a novel natural product-inspired scaffold capable of inhibiting Clostridioides difficile in vitroen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2021-05-04en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Veterinary Medicineen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/CVM T&R Facultyen

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